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JPH0694456B2 - 1'ω-mercaptopropanamide and its salt, method for producing the same, and drug containing the same - Google Patents
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JPH0694456B2 - 1'ω-mercaptopropanamide and its salt, method for producing the same, and drug containing the same - Google Patents

1'ω-mercaptopropanamide and its salt, method for producing the same, and drug containing the same

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Publication number
JPH0694456B2
JPH0694456B2 JP60059719A JP5971985A JPH0694456B2 JP H0694456 B2 JPH0694456 B2 JP H0694456B2 JP 60059719 A JP60059719 A JP 60059719A JP 5971985 A JP5971985 A JP 5971985A JP H0694456 B2 JPH0694456 B2 JP H0694456B2
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formula
carbon atoms
radical
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hydrogen atom
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JPS60222455A (en
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フランソワーズ・ドレバレ
ジヤン・ポール・ブベール
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ルセル‐ユクラフ
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyridine Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

For for the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE 1. Compounds with the formula (I) : see diagramm : EP0159254,P17,F1 in which R1 represents a hydrogen atom or a see diagramm : EP0159254,P17,F2 radical, R'1 being an alkyl radical containing from 1 to 5 carbon atoms or an aryl radical possibly substituted by a hydroxy radical, an alkyl radical containing from 1 to 5 carbon atoms, an alkoxy radical containing form 1 to 5 carbon atoms, the nitro radical or a halogen atom, n represents a whole number variable from 1 to 5, R2 , represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms, an aryl or arylalkyl radical containing from 6 to 15 carbon atoms, possibly substituted by an alkyl radical containing from 1 to 5 carbon atoms, an alkoxyl radical containing from 1 to 5 carbon atoms, a hydroxyl radical, a halogen atom or a trifluoromethyl radical, m represents a whole number variable from 0 to 5, R3 represents : - either a saturated cyclic radical containing from 3 to 12 carbon atoms, which can be fused to a phenyl radical, R3 however not being able to represent a cyclohexyl radical when R2 and R1 represent at the same time a hydrogen atom and n=1 and m=O ; - or a phenyl radical possibly substituted by one or more radicals chosen from the following radicals : alkyl containing 1 to 5 carbon atoms, alkoxy containing from 1 to 5 carbon atoms, hydroxyl, nitro, halogeno, trifluoromethyl and see diagramm : EP0159254,P17,F3 X and X' representing a hydrogen atom or an alkyl radical containing form 1 to 5 carbon atoms or a phenyl radical to which a saturated cyclic radical containing from 5 to 9 carbon atoms is fused ; or a heterocyclic radical chosen from the following radicals : thiazolyl, 4-5-dihydrothiazolyl, pyridinyl, oxazolyl, isoxazolyl, imidazolyl, pyrimidyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, possibly substituted by an alkyl radical containing from 1 to 5 carbon atoms, or a piperidinyl radical substituted by an aralkyl radical containing from 7 to 15 carbon atoms, provided that when R3 représents a phenyl radical possibly substituted by at least one of the radicals previously quoted or when R3 represents one of the heterocyclic radicals mentioned above, possibly substituted by an alkyl radical containing from 1 to 5 cabon atoms, m cannot represent the value 0 and provided that : a) when n=1 or 2, m=1, 2 or 3 and R1 =R2 =H, R3 is not a phenyl radical possibly substituted by one or two alkyl radicals containing form 1 to 5 carbon atoms, b) when m=n=1 and see diagramm : EP0159254,P17,F4 and R2 =CH3 R3 is not a phenyl radical, as well as their addition salts with acids. For the Contracting State : AT 1. Process for preparing compounds with the formula (I) : see diagramm : EP0159254,P18,F1 in which R1 represents a hydrogen atom or a see diagramm : EP0159254,P18,F2 radical, R'1 being an alkyl radical containing from 1 to 5 carbon atoms or an aryl radical possibly substituted a hydroxyl radical, an alkyl radical containing from 1 to 5 carbon atoms, an alkoxy radical containing from 1 to 5 carbon atoms, a nitro radical or a halogen atom, n represents a whole number variable from 1 to 5, R2 represent ts a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms, an aryl or arylalkyl radical containing from 6 to 15 carbon atoms, possibly substituted by an alkyl radical containing from 1 to 5 carbom atoms, an alkoxy radical containing from 1 to 5 carbon atoms, a hydroxyl radical, a halogen atom or a trifluoromethyl radical, m represents a whole number variable from 0 to 5, R3 represents : - either a saturated cyclic radical containing from 3 to 12 carbon atoms, which can be fused to a phenyl radical, R3 howerer not being able to represent a cyclohexyl radical when R2 and R1 represent at the same time a hydrogen atom and n=1 and m=0 ; - or a phenyl radical possibly substituted by one or more radicals chosen from the following radicals : alkyl containing 1 to carbon atoms, alkoxy containing from 1 to 5 carbon atoms, hydroxyl, nitro, halogeno, trifluoromethyl and see diagramm : EP0159254,P18,F3 X and X' representing a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms or a phenyl radical to which a saturated cyclic radical containing from 5 to 9 carbon atoms is fused ; or a heterocyclic radical chosen from the following radicals : thiazolyl, 4-5-dihydrothiazolyl, pyridinyl, oxazolyl, isoxazolyl, imidazolyl, pyrimidyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, possibly substituted by an alkyl radical containing from 1 to 5 carbon atoms, or a piperidinyl radical substituted by an aralkyl radical containing from 7 to 15 carbon atoms, provided that when R3 represents a phenyl radical possibly substituted by at least one of the radicals previously quoted or when R3 represents one of the heterocyclic radicals mentioned above, possibly substituted by an alkyl radical containing from 1 to 5 carbon atoms, m cannot represent the value 0 and provided that : a) when n=1 or 2, m=1, 2 or 3 and R1 =R2 =H, R3 is not a phenyl radical possibly substituted by one or two alkyl radicals containing from 1 to 5 carbon atoms, b) when m=n=1 and see diagramm : EP0159254,P19,F4 and R2 =CH3 R3 is not a phenyl radical, as well as their addition salts with acids, characterized in that - to prepare compounds with the formula (I) in which R1 , R2 and R3 and m have the previously given significance and in which n=1 as well as their addition salts with acids, an acid with the formula (II) : see diagramm : EP0159254,P19,F5 in which R'1 and R2 have the significances already indicated, or a functional derivative of this acid, is submitted to the action of a product with the formula (III) : H2 N-(CH2 )m -R3 in which R3 and m have the significances already indicated, so as to obtain a product with the formula (I), in which R1 = see diagramm : EP0159254,P19,F6 as well as R2 , R3 and m having the significances already indicated and in which n=1, which products with the formula (I) are saponified, if necessary or desired, so as to obtain a product with the formula (I) in which R1 represents a hydrogen atom and which products with the formula (I) are salified, if necessary or desired, by the action of an acid in order to form the salts, - to prepare the compounds with the formula (I) in which R1 , R2 and R3 and m have the previously given significance and in which n represents a whole number variable from 1 to 3, an acid with the formula (IV) : see diagramm : EP0159254,P19,F7 in which X is a halogen atom, and in which n and R2 have the significances given above, or a functional derivative of this acid, is submitted to the action of a product with the formula (III) H2 N(CH2 )m R3 as defined previously, so as to obtain a product with the formula (V) : see diagramm : EP0159254,P19,F8 in which X, n, m, R2 and R3 have the previous significances, which is submitted to the action of the anion of a thioacid with the formula (VI) : see diagramm : EP0159254,P19,F9 in which R'1 is defined as previously, so as to obtain a product with the formula (I) in which see diagramm : EP0159254,P19,F10 R'1 , R2 , R3 n and m having the significances given above, which product with the formula (I) is saponified, if necessary or desired, so as to obtain a product with the formula (I) in which R1 represents a hydrogen atom and which products with the formula (I) are salified, if necessary or desired, by the action of an acid so as to form the salts.

Description

【発明の詳細な説明】 本発明は、ω−メルカプトプロパンアミドの新規な誘導
体及びその同族体、その製造方法、薬剤としてのその使
用、並びにそれを含有する組成物に関するものである。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel derivatives of ω-mercaptopropanamide and its homologues, a process for their preparation, their use as medicaments and compositions containing them.

本発明の主題は、式（Ｉ）： ［式中、R1は水素原子又は を示し、 Ｒ′１は１〜５個の炭素原子を有するアルキル基であ
り、ｎは１の整数を示し、R2は水素原子、１〜５個の炭
素原子を有するアルキル基又はアリールアルキル基を示
し、ｍは０〜２の範囲で変化しうる整数を示し、R3は３
〜12個の炭素原子を有するシクロアルキル基を示すが、
R2及びR1が同時に水素原子を示しさらにｎ＝１かつｍ＝
０である場合にはシクロヘキシル基を示すことができ
ず、又はR3はフェニル、ジヒドロインデニル、ナフチル
若しくはテトラヒドロナフチル基を示し、又はR3は2,3
若しくは４−ピリジニル基を示し、又はフェニルメチル
基により置換されたピペリジニル基を示し、ただし （ａ） ｍ＝ｎ＝１かつR1=R2=Ｈ （ｂ） ｍ＝ｎ＝１、 かつR2=CH3である場合、 R3はフェニル基でない］ を有する化合物並びにその酸付加塩である。The subject of the invention is the formula (I): [In the formula, R 1 is a hydrogen atom or R ′ 1 is an alkyl group having 1 to 5 carbon atoms, n is an integer of 1, R 2 is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms or an arylalkyl group. , M is an integer that can vary in the range of 0 to 2, and R 3 is 3
Represents a cycloalkyl group having ~ 12 carbon atoms,
R 2 and R 1 simultaneously represent a hydrogen atom, and n = 1 and m =
When it is 0, it cannot represent a cyclohexyl group, or R 3 represents a phenyl, dihydroindenyl, naphthyl or tetrahydronaphthyl group, or R 3 represents 2,3
Or a 4-pyridinyl group, or a piperidinyl group substituted with a phenylmethyl group, wherein (a) m = n = 1 and R 1 = R 2 = H (b) m = n = 1, And R 2 ═CH 3 , R 3 is not a phenyl group] and acid addition salts thereof.

R1が を示す場合、Ｒ′１は好ましくはメチル若しくはエチル
基である。R 1 is When showing a, R '1 is preferably a methyl or ethyl group.

R2がアルキル基を示す場合、これは好ましくはメチル、
エチル、ｎ−プロピル、ｎ−ブチル、ｎ−ペンチル、イ
ソプロピル若しくはイソブチル基である。When R 2 represents an alkyl group, this is preferably methyl,
It is an ethyl, n-propyl, n-butyl, n-pentyl, isopropyl or isobutyl group.

R2がアリールアルキル基である場合、これは好ましくは
ベンジル若しくはフエネチル基である。If R 2 is an arylalkyl group, this is preferably a benzyl or phenethyl group.

ｍは好ましくは０、１又は２である。m is preferably 0, 1 or 2.

R3が飽和環式基である場合、これは好ましくはシクロプ
ロパン、シクロブタン、シクロペンタン、シクロヘキサ
ン、シクロヘブタン、シクロオクタン、シクロノナン、
シクロデカン、シクロウンデカン又はシクロドデカン基
である。When R 3 is a saturated cyclic group it is preferably cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane,
It is a cyclodecane, cycloundecane or cyclododecane group.

R3がフエニル基を結合した飽和環式基である場合、この
ように生成される基は、好ましくは1,2,3,4−テトラヒ
ドロ−１−ナフチル基、若しくは1,2,3,4−テトラヒド
ロ−２−ナフチル基又は2,3−ジヒドロ−1H−インデン
−１−イル若しくは2,2−ジヒドロ−1H−インデン−２
−イル基である。When R 3 is a saturated cyclic group having a phenyl group bonded thereto, the group thus generated is preferably a 1,2,3,4-tetrahydro-1-naphthyl group or a 1,2,3,4 group. -Tetrahydro-2-naphthyl group or 2,3-dihydro-1H-inden-1-yl or 2,2-dihydro-1H-indene-2
-It is an yl group.

R3が飽和環式基を係合したフエニル基を示す場合、この
ように生成される基は5,6,7,8−テトラヒドロ−１−ナ
フチル若しくは5,6,7,8−テトラヒドロ−２−ナフチル
又は2,3−ジヒドロ−1H−インデン−４−イル若しくは
2,3−ジヒドロ−1H−インデン−５−イル基であること
が好ましい。When R 3 represents a phenyl group which engages a saturated cyclic group, the group thus produced is 5,6,7,8-tetrahydro-1-naphthyl or 5,6,7,8-tetrahydro-2. -Naphthyl or 2,3-dihydro-1H-inden-4-yl or
It is preferably a 2,3-dihydro-1H-inden-5-yl group.

無機酸又は有機酸によるその付加塩はたとえば塩酸、臭
化水素酸、硝酸、硫酸、燐酸、酢酸、蟻酸、プロピオン
酸、安息香酸、マレイン酸、フマル酸、コハク酸、酒石
酸、クエン酸、修酸、グリオキシル酸、アスパラギン
酸、アルカンスルホン酸、たとえばメタン及びエタンス
ルホン酸、アリールスルホン酸、たとえばベンゼン及び
パラトルエンスルホン酸並びにアリールカルボン酸によ
り生成された塩とすることができる。The addition salt thereof with an inorganic acid or an organic acid is, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, formic acid, propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid. , Glyoxylic acid, aspartic acid, alkane sulfonic acids such as methane and ethane sulfonic acid, aryl sulfonic acids such as benzene and paratoluene sulfonic acid and aryl carboxylic acids.

本発明は、特にその主題としてR1が水素原子である式
（Ｉ）の化合物、並びにR1がアセチル基である式（Ｉ）
の化合物である。The present invention especially relates to compounds of the formula (I) in which R 1 is a hydrogen atom, as well as compounds of the formula (I) in which R 1 is an acetyl group.
Is a compound of.

特に本発明はその主題として、ｎ＝１でありかつR2がベ
ンジル基若しくは水素原子である式（Ｉ）を有する化合
物並びにｍ＝０、１又は２でありかつR3が３〜８個の炭
素原子を有しかつ必要に応じフエニル基に結合した飽和
環式基を示すもの、或いはR3が５〜９個の炭素原子を有
する飽和環式基を結合したフエニル基を示すものであ
る。In particular, the present invention has as its subject matter a compound of formula (I) in which n = 1 and R 2 is a benzyl group or a hydrogen atom, and m = 0, 1 or 2 and R 3 is 3-8. And R 3 represents a saturated cyclic group having a carbon atom and optionally bonded to a phenyl group, or R 3 represents a phenyl group bonded to a saturated cyclic group having 5 to 9 carbon atoms.

さらに本発明は、特にｍ＝１又は２でありかつR3がフエ
ニル又はピリジニル基を示す式（Ｉ）を有する化合物に
関するものである。The invention furthermore relates to compounds of the formula (I) in which m = 1 or 2 and R 3 represents a phenyl or pyridinyl group.

本発明の化合物のうち、後記実施例に示した化合物、特
に次の化合物を挙げることができる： Ｎ−シクロヘキシルα−（メルカプトメチル）ベンゼン
プロパンアミド、 α−（メルカプトメチル）−Ｎ−（２−フエニルエチ
ル）ベンゼンプロパンアミド、 Ｎ−（2,3−ジヒドロ−1H−インデン−２−イル）−３
−メルカプトプロパンアミド、 α−（メルカプトメチル）−Ｎ−（２−ピリジニルメチ
ル）ベンゼンプロパンアミド、 α−（メルカプトメチル）−Ｎ−（３−ピリジニルメチ
ル）ベンゼンプロパンアミド、 α−（メルカプトメチル）−Ｎ−（４−ピリジニルメチ
ル）ベンゼンプロパンアミド、 並びにその酸付加塩である。Among the compounds of the present invention, mention may be made of the compounds shown in Examples below, particularly the following compounds: N-cyclohexyl α- (mercaptomethyl) benzenepropanamide, α- (mercaptomethyl) -N- (2- Phenylethyl) benzenepropanamide, N- (2,3-dihydro-1H-inden-2-yl) -3
-Mercaptopropanamide, α- (mercaptomethyl) -N- (2-pyridinylmethyl) benzenepropanamide, α- (mercaptomethyl) -N- (3-pyridinylmethyl) benzenepropanamide, α- (mercaptomethyl) -N- (4-pyridinylmethyl) benzenepropanamide, and acid addition salts thereof.

さらに本発明はその主題として、R1、R2、R3及びｍが上
記の意味を有しかつｎ＝１である式（Ｉ）の化合物を製
造するに際し式（II）： 〔式中、Ｒ′１及びR2は上記の意味を有する〕 を有する酸又はこの酸の機能的誘導体を式（III）： H2N−（CH2）ｍ−R3 （III） 〔式中、R3及びｍは上記の意味を有する〕 を有する化合物の作用にかけて式（Ｉ）〔式中、 であり、Ｒ′１並びにR2、R3及びｍは上記の意味を有し
かつｎ＝１である〕を有する化合物を得、この式（Ｉ）
を有する化合物を必要に応じ鹸化してR1が水素原子を示
す式（Ｉ）を有する化合物及び必要に応じ酸の作用によ
り塩にされた式（Ｉ）を有する化合物を得ることを特徴
とする式（Ｉ）を有する化合物の製造方法に関するもの
である。The invention further has as its subject matter in the preparation of compounds of formula (I) in which R 1 , R 2 , R 3 and m have the meanings given above and n = 1: [Wherein R ′ 1 and R 2 have the above meanings] or a functional derivative of this acid is represented by the formula (III): H 2 N— (CH 2 ) m—R 3 (III) Wherein R 3 and m have the above meanings] and the formula (I) [in the formula, And R ′ 1 and R 2 , R 3 and m have the meanings given above and n = 1], the compound of formula (I)
Optionally saponifying a compound having the formula (I) in which R 1 represents a hydrogen atom, and optionally a compound having the formula (I) salted by the action of an acid. It relates to a process for preparing a compound having formula (I).

さらに本発明は、R1、R2、R3及びｍが上記の意味を有し
かつｎが１〜５の範囲の整数を示す式（Ｉ）を有する化
合物を製造するに際し、式（IV）： 〔式中、Ｘはハロゲン原子であり、かつｎ及びR2は上記
の意味を有する〕 を有する酸又はその機能的誘導体を前記式（III） H2N（CH1）ｍ−R3を有する化合物の作用にかけて式
（Ｖ）： 〔式中、Ｘ、ｎ、ｍ、R2及びR3に上記の意味を有する〕 の化合物を得、これを式（VI）： 〔式中、Ｒ′１は上記の意味を有する〕 を有するチオ酸の作用にかけて式（Ｉ）〔式中 であり、かつＲ′１、R2、R3、ｎ及びｍは上記の意味を
有する〕を有する化合物を得、この式（Ｉ）を有する化
合物を必要に応じ鹸化してR1が水素原子を示す式（Ｉ）
を有する化合物を得、かつ必要に応じこの式（Ｉ）を有
する化合物を酸の作用により塩にすることを特徴とする
式（Ｉ）を有する化合物の製造方法に関するものであ
る。Further, the present invention provides a compound of the formula (IV) in the production of the compound of the formula (I) in which R 1 , R 2 , R 3 and m have the above meanings and n is an integer in the range of 1 to 5. : [Wherein X is a halogen atom, and n and R 2 have the above meanings] or a functional derivative thereof having the above formula (III) H 2 N (CH 1 ) m-R 3 Depending on the action of the compound, formula (V): [Wherein X, n, m, R 2 and R 3 have the above meanings], and the compound of formula (VI): [Wherein R ′ 1 has the above-mentioned meaning] ## STR1 ## , And the and R '1, R 2, R 3, n and m are to give the compound having the having the meanings described above, saponified R 1 and a hydrogen atom optionally a compound having the formula (I) Formula (I)
The present invention relates to a method for producing a compound having the formula (I), characterized in that the compound having the formula (I) is obtained and, if necessary, the compound having the formula (I) is converted into a salt by the action of an acid.

本発明を実施する好適条件において、上記方法は次のよ
うに行なわれる： 式（II）及び（IV）を有する酸の機能的誘導体は酸の塩
化物である。In the preferred conditions of carrying out the invention, the above process is carried out as follows: The functional derivative of the acid having formulas (II) and (IV) is the chloride of the acid.

式（IV）を有する化合物においてＸは塩素原子である。In the compound having the formula (IV), X is a chlorine atom.

式（II）及び（IV）を有する化合物と式（III）を有す
る化合物との間の縮合反応は、たとえばエチルエーテ
ル、テトラヒドロフラン、ジメチルホルムアミド又は塩
素化溶剤、特に塩化メチレンのような溶剤において行な
われるが、たとえば1,1−ジクロルエタン、クロロホル
ム及び四塩化炭素のような他の溶剤も使用することがで
きる。The condensation reaction between the compounds of formula (II) and (IV) and the compound of formula (III) is carried out, for example, in a solvent such as ethyl ether, tetrahydrofuran, dimethylformamide or a chlorinated solvent, especially methylene chloride. However, other solvents such as 1,1-dichloroethane, chloroform and carbon tetrachloride can also be used.

式（II）を有する化合物と式（III）を有する化合物と
の間の縮合反応は−10℃〜０℃の温度で行なわれる。The condensation reaction between the compound of formula (II) and the compound of formula (III) is carried out at a temperature of -10 ° C to 0 ° C.

である式（Ｉ）を有する化合物の鹸化は、常法により特
にアルカリ金属の水酸化物を使用して達成される。 Saponification of a compound of formula (I) which is: is achieved by conventional methods, especially using hydroxides of alkali metals.

上記式（Ｉ）を有する化合物並びにその塩は有用な薬理
学的性質を有する。これらは、特にエンケフアリナーゼ
の抑制剤として極めて有用な性質を有すると共に、極め
て良好な麻酔活性を有する。The compounds of formula (I) above as well as their salts possess valuable pharmacological properties. These have properties which are extremely useful especially as inhibitors of enkephalinase, and also have extremely good anesthetic activity.

エンケフアリナーゼはジペプチジルカルボキシペプチダ
ーゼであつて、特にメチオニン及びロイシンエンケフア
リンを第三アミノ酸と第四アミノ酸との間で加水分解
し、トリペプチドTyr−Gly−Glyを遊離するものである
〔ジエー・ピー・スウエルツ，アール・ペルドリソツ
ト，ジー・パテイ，エス・デ・ラ・バウメ及びジー・シ
ー・シユワルツ，ヨーロピアン・ジヤーナル・フアーマ
コロジー（1979）、第57巻、第279頁〕。Enkephalinases are dipeptidyl carboxypeptidases, especially those that hydrolyze methionine and leucine enkephalin between the third and fourth amino acids, liberating the tripeptide Tyr-Gly-Gly. • P. Sweltz, Earl Perdrisott, G. Patty, S. de la Baume and G. S. Shiwartz, European Jeanar Pharmakology (1979), 57, 279].

すなわち、エンケフアリナーゼは、麻酔された受容体の
自然内生リガンドであるエンケフアリンの生理学的分解
に直接関与する。エンケフアリンの分解を遅延させる本
発明の化合物は、したがつて痛みに対する生体の防御反
応を刺戟する。That is, enkephalinase is directly involved in the physiological degradation of enkephalin, the natural endogenous ligand of the anesthetized receptor. The compounds according to the invention which delay the degradation of enkephalin thus stimulate the body's protective response to pain.

これらの性質は、治療におけるその使用に適し、したが
つて本発明はさらにその主題として薬物としての上記式
（Ｉ）により定義された化合物並びに医薬上許容しうる
酸によるその付加塩に関する。These properties are suitable for its use in therapy, and therefore the present invention further relates as its subject to the compounds defined by the above formula (I) as drugs and their addition salts with pharmaceutically acceptable acids.

特に本発明は薬剤としての次の化合物を主題とする： Ｎ−シクロヘキシル−α−（メルカプトメチル）ベンゼ
ンプロパンアミド、 α−（メルカプトメチル）−Ｎ−（２−フエニルエチ
ル）ベンゼンプロパンアミド、 Ｎ−（2,3−ジヒドロ−1H−インデン−２−イル）−３
−メルカプトプロパンアミド、 α−（メルカプトメチル）−Ｎ−（２−ピリジニルメチ
ル）ベンゼンプロパンアミド、 α−（メルカプトメチル）−Ｎ−（３−ピリジニルメチ
ル）ベンゼンプロパンアミド、 α−（メルカプトメチル）−Ｎ−（４−ピリジニルメチ
ル）ベンゼンプロパンアミド、並びにその医薬上許容し
うる酸付加塩である。In particular, the present invention is directed to the following compounds as agents: N-cyclohexyl-α- (mercaptomethyl) benzenepropanamide, α- (mercaptomethyl) -N- (2-phenylethyl) benzenepropanamide, N- ( 2,3-dihydro-1H-inden-2-yl) -3
-Mercaptopropanamide, α- (mercaptomethyl) -N- (2-pyridinylmethyl) benzenepropanamide, α- (mercaptomethyl) -N- (3-pyridinylmethyl) benzenepropanamide, α- (mercaptomethyl) -N- (4-pyridinylmethyl) benzenepropanamide, as well as its pharmaceutically acceptable acid addition salts.

本発明の主題である薬剤は筋肉痛、関節痛又は神経痛、
帯状胞疹及び片頭痛の治療、並びにリユーマチ症の治療
に使用することができ、さらに感染及び発熱状態におけ
る補促治療として使用することができる。The agents which are the subject of this invention are muscle pain, arthralgia or neuralgia,
It can be used for the treatment of shingles and migraine, as well as for the treatment of rheumatism, and can also be used as a stimulating treatment in infections and fever.

さらに、本発明は、活性成分として上記の薬剤を含有す
る医薬組成物まで拡大される。Furthermore, the present invention extends to pharmaceutical compositions containing the above agents as active ingredients.

これらの医薬組成物は経口、経腸又は非経口経路で投与
することができ、或いは皮膚及び粘膜に対する局部塗布
による局部経路で施こすこともできる。These pharmaceutical compositions can be administered by the oral, enteral or parenteral route or can be applied by the topical route by topical application to the skin and mucous membranes.

これら組成物は固体若しくは液体とすることができ、現
在たとえば普通錠、糖衣錠、カプセル、顆粒、座薬、注
射用製剤、軟膏、クリーム、ゲル及びエアロゾル製剤の
ような人間医薬に使用されている医薬形態で提供するこ
とができ、これらは常法により製造される。活性成分
は、これら医薬組成物に一般に使用される補形薬たとえ
ばタルク、アラビヤゴム、乳糖、澱粉、ステアリン酸マ
グネシウム、ココア脂、水性若しくは非水性ベヒクル、
動物性若しくは植物性の脂肪物質、パラフイン誘導体、
グリコール、各種の湿潤剤若しくは乳化剤及び保存料と
配合することができる。These compositions may be solid or liquid and are currently in human medicine such as plain tablets, dragees, capsules, granules, suppositories, injectables, ointments, creams, gels and aerosol formulations. And can be provided by a conventional method. The active ingredient may be an excipient commonly used in these pharmaceutical compositions such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles,
Animal or vegetable fatty substances, paraffin derivatives,
It can be combined with glycols, various wetting or emulsifying agents and preservatives.

薬量は特に投与経路、処置すべき症状及び患者に依存し
て変化する。The dosage will vary depending, inter alia, on the route of administration, the condition to be treated and the patient.

たとえば成人において、経口ルートにより毎日20mg〜2g
の活性成分の範囲で変化することができる。For example, in adults, 20 mg to 2 g daily by oral route
The range of active ingredients can vary.

本発明の方法に対する出発化合物として使用される或る
種の式（II）及び（IV）を有する化合物は、オンデツチ
等に係る米国特許第4053651号公報に記載され、かつそ
れにしたがつて製造される。Certain compounds of formulas (II) and (IV) used as starting compounds for the process of the present invention are described and prepared according to U.S. Pat. No. 4,053,651 to Ondetch et al. .

この米国特許に記載されていない式（II）及び（IV）を
有する化合物は、この特許に記載されたように製造する
ことができる。Compounds having formulas (II) and (IV) not described in this US patent can be prepared as described in this patent.

以下の例により本発明を説明するが、これのみ限定され
ない。The present invention is illustrated by the following non-limiting examples.

例1:α〔（アセチルチオ）メチル〕−Ｎ−シクロヘキシ
ルベンゼンプロパンアミド 工程A:α−（アセチルチオメチル）ベンゼンプロパノイ
ルクロライド。Example 1: α [(acetylthio) methyl] -N-cyclohexylbenzenepropanamide Step A: α- (acetylthiomethyl) benzenepropanoyl chloride.

1.21gのα−ベンジルアクリル酸〔シー・マニツヒ等、
ケミカル・ベリヒテ、第57B巻、第1116−８頁（1924）
に記載されかつそれにしたがつて製造される化合物〕を
0.8gのチオ酢酸に溶解し、アルゴン下で室温にて１時間
保ち、100℃で１時間加熱し、次いで過剰のチオ酢酸を
減圧除去する。残留油状物に1.8gの塩化チオニルを０℃
にて撹拌下かつアルゴン下に滴加する。室温にて１晩保
つた後、過剰の塩化チオニルを減圧除去し、50mlのベン
ゼンを加え、次いで減圧下で除去する。残留油を蒸留し
た後、1.87gの求める生成物が得られる。沸点 150℃
（10-2トール） 工程B:α−〔（アセチルチオ）メチル〕−Ｎ−シクロヘ
キシルベンゼンプロパンアミド。1.21 g of α-benzylacrylic acid (See Manithi,
Chemical Berichte, Volume 57B, pp. 1116-8 (1924).
And the compounds produced accordingly.
Dissolve in 0.8 g of thioacetic acid, hold at room temperature under argon for 1 hour, heat at 100 ° C. for 1 hour, then remove excess thioacetic acid under reduced pressure. 1.8 g of thionyl chloride was added to the residual oil at 0 ° C.
Is added dropwise with stirring under argon. After keeping at room temperature overnight, excess thionyl chloride is removed under reduced pressure, 50 ml of benzene are added, and then removed under reduced pressure. After distilling the residual oil, 1.87 g of the expected product are obtained. Boiling point 150 ° C
(10 -2 torr) Step B: α-[(acetylthio) methyl] -N-cyclohexylbenzenepropanamide.

アルゴン下で１時間かけて−５℃〜10℃にて、上記工程
Ａで作成された化合物6.42gを塩化メチレン100ml中に溶
解された4.9gのシクロヘキシルアミンの溶液に加える。
溶剤を30℃にて減圧除去し、残留物を300mlのエーテル
中に溶解し、過し、次いで有機相を0.1N塩酸と酸性炭
酸ナトリウムと水と塩化ナトリウムの飽和溶液とで洗浄
する。有機相を脱水し、過し、そして液を減圧下で
濃縮乾固する。3.8gの第１フラクシヨンの求める生成物
が得られる。このシクロヘキシルアミン塩酸塩を200ml
の塩化メチレンにより溶解し、0.1N塩酸で洗浄し、次い
で有機相を脱水し、分離しかつ減圧濃縮する。3.7gの求
める生成物の第２フラクシヨンが得られる。得られた２
つのフラクシヨンを塩化メチレン150ml中で合しかつ
過し、次いで溶剤を除去した後に減圧下で乾燥する。7.
5gの求める生成物が得られ、これはシリカ上でのクロマ
トグラフイーにより75−25シクロヘキサン−酢酸エチル
混合物で溶出させて、0.35のRf値を示す。6.42 g of the compound prepared in step A above is added to a solution of 4.9 g of cyclohexylamine dissolved in 100 ml of methylene chloride at −5 ° C. to 10 ° C. under argon over 1 hour.
The solvent is removed under reduced pressure at 30 ° C., the residue is taken up in 300 ml of ether and passed, then the organic phase is washed with 0.1N hydrochloric acid, sodium acid carbonate, water and a saturated solution of sodium chloride. The organic phase is dried, passed and the liquid is concentrated to dryness under reduced pressure. 3.8 g of the desired product of the first fraction is obtained. 200 ml of this cyclohexylamine hydrochloride
Dissolved in methylene chloride, washed with 0.1N hydrochloric acid, then the organic phase is dried, separated and concentrated under reduced pressure. 3.7 g of a second fraction of the desired product is obtained. Obtained 2
The two fractions are combined and filtered in 150 ml of methylene chloride and then freed from the solvent and dried under reduced pressure. 7.
5 g of the expected product are obtained, which is chromatographed on silica eluting with a 75-25 cyclohexane-ethyl acetate mixture and shows an Rf value of 0.35.

例2:N−シクロヘキシルα−（メルカプトメチル）ベン
ゼンプロパンアミド −10℃かつアルゴン下にて１時間かけて235.7mlの0.1N
水酸化ナトリウムを250mlのメタノール中における上記
例１の化合物7.5gの溶液に導入する。これを徐々に０℃
まで戻した後、235.7mlの0.1N塩酸をこの温度で30分か
けて６〜７のpHまで加える。メタノールを減圧除去し、
次いで塩化メチレンにより抽出を行なう。有機相を脱水
し、そして減圧下で濃縮乾固させる。6.5gの粗生成物が
得られ、これをシリカ上でクロマトグラフにかけ、シク
ロヘキサンと塩化メチレンとの混合物（１−９）で溶出
させる。3.1gの求める生成物が得られ、融点は117℃で
ある。Example 2: N-cyclohexyl α- (mercaptomethyl) benzenepropanamide 235.7 ml 0.1N over 1 hour at -10 ° C and argon.
Sodium hydroxide is introduced into a solution of 7.5 g of the compound of Example 1 above in 250 ml of methanol. Gradually add this to 0 ℃
After reconstitution to 235.7 ml 0.1N hydrochloric acid is added at this temperature over 30 minutes to a pH of 6-7. Remove the methanol under reduced pressure,
Then extraction is carried out with methylene chloride. The organic phase is dried and concentrated to dryness under reduced pressure. 6.5 g of crude product are obtained, which is chromatographed on silica, eluting with a mixture of cyclohexane and methylene chloride (1-9). 3.1 g of the expected product are obtained, melting point is 117.degree.

分析値:C16H23NOS:分子量277.431 計算値:C％69.3 Ｈ％8.4 Ｎ％5.1 Ｓ％11.6 実測値： 69.4 8.5 4.9 11.6 例3:α−〔（アセチルチオ）メチル〕−Ｎ−シクロヘキ
シルプロパンアミド 工程A:3−アセチルチオ−２−メチルプロパン酸クロラ
イド。Analytical value: C 16 H 23 NOS: molecular weight 277.431 Calculated value: C% 69.3 H% 8.4 N% 5.1 S% 11.6 Actual value: 69.4 8.5 4.9 11.6 Example 3: α-[(acetylthio) methyl] -N-cyclohexylpropanamide Step A: 3-Acetylthio-2-methylpropanoic acid chloride.

261gの３−アセチルチオ−２−メチルプロパン酸〔スケ
ルドン・エヌ・ルイス、J.Met,Chem、第４巻、第571
頁、（1971）にしたがつて製造〕を520mlの塩化チオニ
ル中へ導入する。この溶液を徐々に３時間かけて還流が
得られるまで加熱しかつこの温度に２時間保ち、強力な
ガスの発生を生ぜしめる。塩化チオニルを留去した後、
油状物が得られ、これを106℃にて15mmHgの減圧下に蒸
留する。このようにして、182gの求める生成物が得ら
れ、これを次の工程にそのまま使用する。261 g of 3-acetylthio-2-methylpropanoic acid [Skeldon N. Lewis, J. Met, Chem, Vol. 4, 571]
Manufactured according to page (1971)] in 520 ml of thionyl chloride. The solution is gradually heated over 3 hours until reflux is obtained and kept at this temperature for 2 hours, causing the generation of a strong gas. After distilling off thionyl chloride,
An oil is obtained, which is distilled at 106 ° C. under a reduced pressure of 15 mm Hg. In this way 182 g of the expected product is obtained, which is used as such in the next step.

工程B:α−〔（アセチルチオ）メチル〕−Ｎ−シクロヘ
キシルプロパンアミド。Step B: α-[(acetylthio) methyl] -N-cyclohexylpropanamide.

30分間かけてアルゴン下かつ撹拌下に2gの工程Ａで調製
した生成物を塩化メチレン100ml中のシクロヘキシルア
ミン220gの−９℃まで冷却された溶液中に導入する。Over a period of 30 minutes under argon and with stirring, 2 g of the product prepared in step A are introduced into a solution of 220 g of cyclohexylamine in 100 ml of methylene chloride cooled to -9 ° C.

撹拌を−５℃にて２時間維持し、次いで室温にて１時間
保ち、次いで塩化メチレンを減圧下に除去する。残留物
を300mlのエーテルで溶解させ、15分間撹拌する。シク
ロヘキシルアミン塩酸塩を過し、液を1N塩酸と水と
酸性炭酸ナトリウムの飽和溶液と次いで水とで洗浄す
る。有機相を脱水し、過し、そして減圧下で濃縮す
る。残留物を100mlのペンタン中でトリチル化し、分離
し、ペンタンで洗浄し、減圧乾燥して2.102gの生成物、
融点82−83℃を得る。Stirring is maintained at −5 ° C. for 2 hours, then at room temperature for 1 hour, then the methylene chloride is removed under reduced pressure. The residue is dissolved with 300 ml of ether and stirred for 15 minutes. Pass cyclohexylamine hydrochloride and wash the liquor with 1N hydrochloric acid, water, a saturated solution of sodium acid carbonate, and then water. The organic phase is dried, passed and concentrated under reduced pressure. The residue was tritylated in 100 ml pentane, separated, washed with pentane and dried under vacuum to give 2.102 g of product,
A melting point of 82-83 ° C. is obtained.

例4:N−シクロヘキシル−３−メルカプト−２−メチル
プロパンアミド ５℃で30分間かけてアルゴン下かつ撹拌下に、85mlの0.
1N水酸化ナトリウムを125mlのメタノール中における例
３で得られた生成物2.066gの溶液中に導入する。Example 4: N-cyclohexyl-3-mercapto-2-methylpropanamide 85 ml of 0.5 at 30C under argon and stirring.
1N sodium hydroxide is introduced into a solution of 2.066 g of the product obtained in Example 3 in 125 ml of methanol.

撹拌を−５℃にて１時間維持し、次いで０℃にてpH5−
６まで0.1N塩酸85mlで酸性化した後、メタノールを減圧
除去する。分離し、水洗しかつ減圧乾燥することにより
残留物を得、これをシリカ上でクロマトグラフにかけ、
クロロホルムで溶出させる。1.351gの求める生成物が得
られる。融点115℃。Stirring is maintained at -5 ° C for 1 hour and then at 0 ° C pH 5-
After acidification up to 6 with 85 ml of 0.1N hydrochloric acid, the methanol is removed under reduced pressure. Separated, washed with water and dried under reduced pressure to give a residue, which was chromatographed on silica,
Elute with chloroform. 1.351 g of the expected product is obtained. Melting point 115 ° C.

分析値:C10H19NOS、分子量:201.333 計算値:C％59.66 Ｈ％9.51 Ｎ％6.96 Ｓ％15.92 実測置： 59.7 9.6 6.9 15.8 例5:α−〔（アセチルチオ）メチル〕−Ｎ−（フエニル
メチル）ベンゼンプロパンアミド 塩化メチレン250ml中の例１の工程Ａに記載したように
調製したα−（アセチルチオメチル）ベンゼンプロパノ
イルクロライド6.42gの溶液を、約−５℃にて30分間か
けて塩化メチレン250ml中に溶解された5.36gのベンジル
アミンに導入する。Analytical value: C 10 H 19 NOS, molecular weight: 201.333 Calculated value: C% 59.66 H% 9.51 N% 6.96 S% 15.92 Measurement position: 59.7 9.6 6.9 15.8 Example 5: α-[(acetylthio) methyl] -N- (phenylmethyl) ) Benzenepropanamide A solution of 6.42 g of α- (acetylthiomethyl) benzenepropanoyl chloride prepared as described in Step A of Example 1 in 250 ml of methylene chloride was added to methylene chloride at about -5 ° C over 30 minutes. Introduce 5.36 g of benzylamine dissolved in 250 ml.

室温に16時間放置した後、溶剤を減圧除去し、そしてベ
ンジルアミン塩酸塩を400mlのエーテルの添加により沈
殿させる。生成した沈殿物を別し、液を0.1N塩酸で
洗浄し、次いで水によりpH＝６まで洗浄し、次いで脱水
しかつ溶剤を除去する。得られた残留物をシリカ上でク
ロマトグラフにかけ、クロロホルムと酢酸エチルとの混
合物（98−２）で溶出させる。8.8gの求める生成物が得
られる。融点90℃。After standing at room temperature for 16 hours, the solvent is removed under reduced pressure and benzylamine hydrochloride is precipitated by the addition of 400 ml ether. The precipitate formed is separated off, the liquor is washed with 0.1N hydrochloric acid and then with water until pH = 6, then dehydrated and freed from the solvent. The residue obtained is chromatographed on silica, eluting with a mixture of chloroform and ethyl acetate (98-2). 8.8 g of the expected product are obtained. Melting point 90 ° C.

例6:α−（メルカプトメチル）−Ｎ−（フエニルメチ
ル）ベンゼンプロパンアミド 約０゜〜−５℃にてアルゴン下かつ撹拌下に１時間かけ
て、269mlの0.1N水酸化ナトリウム溶液をメタノール250
mlにおける例５で得られた生成物8.8gの溶液中に導入す
る。１時間かけて０℃まで戻した後、269mlの0.1N塩酸
をさらに１時間かけて加える。メタノールを減圧除去
し、そして水相を塩化メチレンで抽出し、脱水し、過
し、かつ減圧下で濃縮乾固させる。6.95gの残留物が油
状物として得られ、これをシリカ上でクロマトグラフに
かけ、塩化メチレンとシクロヘキサンとの混合物（８−
２）で溶出させる。3.5gの求める生成物が得られる。融
点70℃。Example 6: α- (mercaptomethyl) -N- (phenylmethyl) benzenepropanamide 269 ml of 0.1N sodium hydroxide solution in methanol 250 at about 0 ° to -5 ° C under argon and stirring for 1 hour.
8.8 g of the product obtained in Example 5 in ml are introduced into the solution. After returning to 0 ° C. over 1 hour, 269 ml of 0.1N hydrochloric acid is added over 1 hour. The methanol is removed under reduced pressure and the aqueous phase is extracted with methylene chloride, dried, filtered and concentrated to dryness under reduced pressure. 6.95 g of residue were obtained as an oil, which was chromatographed on silica and a mixture of methylene chloride and cyclohexane (8-
Elute in 2). 3.5 g of the expected product are obtained. Melting point 70 ° C.

分析値:C17H19NOS、分子量:285.411 計算値:C％71.5 Ｈ％6.7 Ｎ％4.9 Ｓ％11.2 実測値： 71.7 6.9 4.8 11.2 例7:α−〔（アセチルチオ）メチル〕−Ｎ−（２−フエ
ニルエチル）−ベンゼンプロパンアミド 塩化メチレン250mlにおける6.059gのフエニルエチルア
ミンの溶液中へ、30分かけて０℃にて撹拌下かつアルゴ
ン下において、例１の工程Ａに記載したように調製した
250mlの塩化メチレンにおけるα−（アセチルチオメチ
ル）ベンゼンプロパノイルクロライド6.419gの溶液を導
入しかつ16時間撹拌し、その間温度を20℃まで上昇させ
る。生成されたフエニルエチルアミン塩酸塩を過し、
液を1N塩酸と水と酸性炭酸ナトリウムの飽和溶液とで
洗浄し、次いでpH6−７まで水洗する。有機相を脱水
し、次いで過し、減圧下で濃縮乾固する。得られた残
留物を50mlのエーテル中でトリチル化し、次いで分離
し、エーテル洗浄し、減圧下で乾燥して5.476gの生成物
を得る。融点64℃。Analytical value: C 17 H 19 NOS, molecular weight: 285.411 Calculated value: C% 71.5 H% 6.7 N% 4.9 S% 11.2 Actual value: 71.7 6.9 4.8 11.2 Example 7: α-[(acetylthio) methyl] -N- (2 -Phenylethyl) -benzenepropanamide Prepared as described in step A of Example 1 into a solution of 6.059 g of phenylethylamine in 250 ml of methylene chloride at 0 ° C for 30 minutes with stirring and under argon.
A solution of 6.419 g of α- (acetylthiomethyl) benzenepropanoyl chloride in 250 ml of methylene chloride is introduced and stirred for 16 hours while the temperature is raised to 20 ° C. Pass the phenylethylamine hydrochloride produced,
The solution is washed with 1N hydrochloric acid, water and a saturated solution of sodium acid carbonate, and then washed with water to pH 6-7. The organic phase is dried, then filtered and concentrated to dryness under reduced pressure. The residue obtained is tritylated in 50 ml of ether, then separated, washed with ether and dried under reduced pressure to give 5.476 g of product. Melting point 64 ° C.

例8:α−（メルカプトメチル）−Ｎ−（２−フエニルエ
チル）ベンゼンプロパンアミド 160mlの0.1N水酸化ナトリウムと、325mlのメタノールに
おける例７で得られた生成物5.442gの溶液とから出発
し、例４に記載したように操作して、3.529gの求める生
成物を得る。融点70℃。Example 8: α- (mercaptomethyl) -N- (2-phenylethyl) benzenepropanamide Starting from 160 ml of 0.1N sodium hydroxide and a solution of 5.442 g of the product obtained in Example 7 in 325 ml of methanol, Operating as described in Example 4, 3.529 g of the desired product is obtained. Melting point 70 ° C.

分析値:C18H21NOS、分子量:299.438 計算値:C％72.20 Ｈ％7.07 Ｎ％4.68 Ｓ％10.7 実測値： 72.5 7.2 4.7 10.6 例9:3−（アセチルチオ）−Ｎ−（２−フエニルエチ
ル）プロパンアミド 工程A:3−（アセチルチオ）プロパン酸クロライド。Analytical value: C 18 H 21 NOS, molecular weight: 299.438 Calculated value: C% 72.20 H% 7.07 N% 4.68 S% 10.7 Actual value: 72.5 7.2 4.7 10.6 Example 9: 3- (acetylthio) -N- (2-phenylethyl) Propanamide Step A: 3- (acetylthio) propanoic acid chloride.

30分間かけてアルゴン下かつ撹拌下に100mlのチオ酢酸
を75mlのアクリル酸中へ導入し、その間温度を22℃〜35
℃の範囲に維持する。撹拌を室温にて１晩、次いで100
℃にて1.5時間続ける。温度を室温まで低下させると固
体が再結晶化する。過剰のチオ酢酸を減圧除去し、170g
の３−（アセチルチオ）プロパン酸を得る（融点40−45
℃）。次いで、これを170mlの無水エチルエーテル中に
溶解し、アルゴン下かつ撹拌下に130mlの塩化チオニル
を加える。室温で１晩撹拌した後、ベンゼンと同伴させ
ながら過剰の塩化チオニルを減圧除去する。100 ml of thioacetic acid are introduced into 75 ml of acrylic acid under argon and stirring over 30 minutes, while the temperature is between 22 ° C and 35 ° C.
Keep in the ° C range. Stir at room temperature overnight, then 100
Continue for 1.5 hours at ℃. The solid recrystallises when the temperature is reduced to room temperature. Excess thioacetic acid was removed under reduced pressure, 170 g
To give 3- (acetylthio) propanoic acid (melting point 40-45
C). It is then dissolved in 170 ml of anhydrous ethyl ether and 130 ml of thionyl chloride are added under argon and with stirring. After stirring overnight at room temperature, excess thionyl chloride is removed under reduced pressure with benzene.

残留油状物を留除した後、146.9gの求める生成物が得ら
れる（0.5mmHgにおける沸点63−64℃）。After distilling off the residual oil, 146.9 g of the expected product are obtained (boiling point 63-64 ° C. at 0.5 mmHg).

工程B:3−（アセチルチオ）−Ｎ−（２−フエニルエチ
ル）プロパンアミド 工程Ａに記載したように調製した塩化メチレン150mlに
おける３−アセチルチオプロパン酸クロライド2.314gの
溶液と、塩化メチレン150mlにおけるフエニルエチルア
ミン3.366gの溶液とから出発し、例５に記載したように
操作して、シリカ上でクロマトグラフにかけかつ塩化メ
チレンと酢酸エチルとの混合物（95−５）にて溶出させ
た後、2.177gの求める生成物が得られる。融点69−70
℃。Step B: 3- (Acetylthio) -N- (2-phenylethyl) propanamide A solution of 2.314 g 3-acetylthiopropanoic acid chloride in 150 ml methylene chloride prepared as described in Step A and phenyl in 150 ml methylene chloride. 2.177 g, after starting with a solution of 3.366 g of ethylamine and operating as described in Example 5, chromatographing on silica and eluting with a mixture of methylene chloride and ethyl acetate (95-5). The desired product is obtained. Melting point 69-70
° C.

例10:3−メルカプト−Ｎ−（２−フエニルエチル）プロ
パンアミド メタノール120mlにおける例９の生成物2.14gの溶液と8
5.1mlの0.1N水酸化ナトリウムとから出発し、例４に記
載したように操作して1.349gの求める生成物を得る。Example 10: 3-Mercapto-N- (2-phenylethyl) propanamide A solution of 2.14 g of the product of Example 9 in 120 ml of methanol and 8
Starting with 5.1 ml of 0.1 N sodium hydroxide, operating as described in Example 4, gives 1.349 g of the expected product.

分析値:C11H15NOS、分子量:209.313 計算値:C％63.12 Ｈ％7.22 Ｎ％6.69 Ｓ％15.32 実測値： 63.0 7.3 6.6 15.0 例11:3−アセチルチオ−Ｎ−（2.3−ジヒドロ−1H−イ
ンデン−２−イル）プロパンアミド ２−アミノインダン塩酸塩3.036gの溶液と塩化メチレン
150mlにおけるトリエチルアミン45ミリモルと2.500gの
例９の工程Ａに記載したように調製した３−（アセチル
チオ）プロパン酸クロライドとから出発し、例３に記載
したように手順を行なつて3.88gの求める生成物を得
る。融点74℃。Analytical value: C 11 H 15 NOS, molecular weight: 209.313 Calculated value: C% 63.12 H% 7.22 N% 6.69 S% 15.32 Found value: 63.0 7.3 6.6 15.0 Example 11: 3-acetylthio-N- (2.3-dihydro-1H- Inden-2-yl) propanamide 2-aminoindan hydrochloride solution of 3.036 g and methylene chloride
Starting with 45 mmol of triethylamine in 150 ml and 2.500 g of 3- (acetylthio) propanoic acid chloride prepared as described in step A of example 9 and following the procedure as described in example 3 to obtain 3.88 g. The product is obtained. Melting point 74 ° C.

例12:N−（2,3−ジヒドロ−1H−インデン−２−イル）
−３−メルカプトプロパンアミド −７℃〜−10℃の範囲で30分かけてアルゴン下かつ撹拌
下に150mlの0.1N水酸化ナトリウムをメタノール230mlに
おける例11で得られた生成物3.87gの溶液に加える。沈
殿物が得られ、これを350mlのメタノールの添加により
溶解し、その間温度を維持すると共に撹拌を1.5時間続
けた。Example 12: N- (2,3-dihydro-1H-inden-2-yl)
-3-Mercaptopropanamide 150 ml of 0.1 N sodium hydroxide in a solution of 3.87 g of the product obtained in Example 11 in 230 ml of methanol under argon and stirring in the range of -7 ° C to -10 ° C for 30 minutes. Add. A precipitate was obtained, which was dissolved by the addition of 350 ml of methanol while maintaining the temperature and stirring for 1.5 hours.

0.1N塩酸溶液にて同温度で中和した後、メタノールを除
去して、そして沈殿物を過し、次いでシリカ上でクロ
マトグラフにかけ、シクロヘキサンと酢酸エチルとの混
合物（60−40）で溶出させて1.7gの生成物を得る。融点
88℃。After neutralization with 0.1N hydrochloric acid solution at the same temperature, the methanol was removed and the precipitate was filtered off, then chromatographed on silica, eluting with a mixture of cyclohexane and ethyl acetate (60-40). Gives 1.7 g of product. Melting point
88 ° C.

分析値:C12H15NOS、分子量:221.323 計算値:C％65.12 Ｈ％6.83 Ｓ％14.49 Ｎ％6.33 実測値： 65.4 6.9 14.5 6.4 例13:3−（アセチルチオ）−Ｎ−（2.3−ジヒドロ−1H
−インデン−１−イル）プロパンアミド 塩化メチレン150mlにおける１−アミノインダン3.463g
の溶液と塩化メチレン150mlにおける例９の工程Ａのよ
うに調製した３−（アセチルチオ）プロパン酸クロライ
ド2.166gの溶液とから出発し、例３に記載したように手
順を行なつて3.183gの求める生成物を得る。融点109
℃。Analytical value: C 12 H 15 NOS, molecular weight: 221.323 Calculated value: C% 65.12 H% 6.83 S% 14.49 N% 6.33 Found value: 65.4 6.9 14.5 6.4 Example 13: 3- (acetylthio) -N- (2.3-dihydro- 1H
-Inden-1-yl) propanamide 3.463 g of 1-aminoindan in 150 ml of methylene chloride
Starting with a solution of 2.166 g of 3- (acetylthio) propanoic acid chloride prepared as in Step A of Example 9 in 150 ml of methylene chloride and following the procedure as described in Example 3 to obtain 3.183 g. The product is obtained. Melting point 109
° C.

例14:N−（2,3−ジヒドロ−1H−インデン−１−イル）
−３−メルカプトプロパンアミド 119mlの0.1N水酸化ナトリウムとメタノール170mlにおけ
る例13で得られた生成物3.128gとから出発し、例12に記
載したように手順を−６℃にて行なう。シリカ上でクロ
マトグラフにかけ、塩化メチレンと酢酸エチルとの混合
物（95−５）で溶出させた後、2.022gの求める生成物が
得られる。融点99℃。Example 14: N- (2,3-dihydro-1H-inden-1-yl)
-3-Mercaptopropanamide Starting from 119 ml of 0.1 N sodium hydroxide and 3.128 g of the product obtained in example 13 in 170 ml of methanol, the procedure is carried out as described in example 12 at -6 ° C. After chromatography on silica, eluting with a mixture of methylene chloride and ethyl acetate (95-5), 2.022 g of the expected product is obtained. Melting point 99 ° C.

分析値:C12H15NOS、分子量:221.324 計算値:C％65.12 Ｈ％6.83 Ｎ％6.33 Ｓ％14.49 実測値： 65.3 6.39 6.2 14.8 例15:3−（アセチルチオ）−Ｎ−（1,2,3,4−テトラヒ
ドロ−１−ナフチル）プロパンアミド −７℃〜−10℃にて30分間かけてアルゴン下かつ撹拌下
に、塩化メチレン150mlにおける1,2,3,4−テトラヒドロ
ナフチルアミン4.418gの溶液を塩化メチレン150mlにお
ける例９の工程Ａに示したように調製した３−（アセチ
ルチオ）プロパン酸クロマイド2.5gの溶液に加える。得
られた沈殿を過し、次いで１のエーテル中に懸濁さ
せ、そして30℃にて３時間撹拌する。沈殿物を過し、
得られた２つの液を合する。溶剤を減圧下（20℃）で
除去し、得られた残留物を200mlの塩化メチレン中に溶
解させ、0.1N塩酸と酸性炭酸ナトリウムの飽和溶液と次
いで水とで洗浄する。脱水した後、溶剤を30℃にて減圧
除去し、次いで残留物を１のエーテル中に溶解させ、
これを沈殿物が観察されるまで除去する。７℃にて３時
間放置した後、最初のロツトを別する。100mlのペン
タンを液に加え、次いでこれを７℃にて３時間放置
し、次いで過し、第２のロツトを得る。これら２つの
ロツトを水銀柱10-2mmの下で16時間乾燥する。Analytical value: C 12 H 15 NOS, molecular weight: 221.324 Calculated value: C% 65.12 H% 6.83 N% 6.33 S% 14.49 Found value: 65.3 6.39 6.2 14.8 Example 15: 3- (acetylthio) -N- (1,2, 3,4-Tetrahydro-1-naphthyl) propanamide A solution of 4.418 g of 1,2,3,4-tetrahydronaphthylamine in 150 ml of methylene chloride under argon and stirring at -7 ° C to -10 ° C for 30 minutes. Is added to a solution of 2.5 g of 3- (acetylthio) propanoic acid chromide prepared as described in Step A of Example 9 in 150 ml of methylene chloride. The precipitate obtained is filtered off, then suspended in 1 ether and stirred at 30 ° C. for 3 hours. Have a deposit,
The two liquids obtained are combined. The solvent is removed under reduced pressure (20 ° C.), the residue obtained is dissolved in 200 ml of methylene chloride and washed with 0.1N hydrochloric acid and a saturated solution of sodium acid carbonate and then with water. After dehydration, the solvent was removed under reduced pressure at 30 ° C., then the residue was dissolved in 1 ether,
This is removed until a precipitate is observed. After standing at 7 ° C for 3 hours, the first lot is separated. 100 ml of pentane are added to the liquor, which is then left at 7 ° C. for 3 hours and then passed to obtain a second lot. The two lots are dried under 10 -2 mm of mercury for 16 hours.

2.432gの求める生成物が第１ロツトから得られ、0.905g
が第２ロツトから得られる。これら２つのロツトのそれ
ぞれは、シリカ上でのクロマトグラフにおいてシクロヘ
キサンと酢酸エチルとの混合物（80−20）で溶出させる
と0.14のRf値を示す。融点108−109℃。2.432 g of desired product was obtained from the first lot, 0.905 g
Is obtained from the second lot. Each of these two rods shows an Rf value of 0.14 when chromatographed on silica, eluting with a mixture of cyclohexane and ethyl acetate (80-20). Melting point 108-109 [deg.] C.

例16:3−メルカプト−Ｎ−（1,2,3,4−テトラヒドロ−
１−ナフチル）プロパンアミド メタノール250mlにおける例15で得られた生成物3.337g
と120mlの0.1N水酸化ナトリウムとから出発し、例４に
記載したように操作して1.850gの求める生成物が得られ
る。融点94℃。Example 16: 3-Mercapto-N- (1,2,3,4-tetrahydro-
1-naphthyl) propanamide 3.337 g of the product obtained in Example 15 in 250 ml of methanol
Starting with and 120 ml 0.1 N sodium hydroxide, operating as described in Example 4, 1.850 g of the expected product are obtained. Melting point 94 ° C.

分析値:C13H17NOS、分子量235.350 計算値:C％66.34 Ｈ％7.28 Ｎ％5.96 Ｓ％13.62 実測値： 66.4 7.4 6 13.6 例17:3−アセチルチオ−Ｎ−（5,6,7,8−テトラヒドロ
−１−ナフチル）プロパンアミド −７℃〜−10℃で30分間かけてアルゴン下かつ撹拌下
に、塩化メチレン150mlにおける例９の工程Ａに記載し
たように作成した３−（アセチルチオ）プロパン酸クロ
マイド2.5gの溶液を塩化メチレン150mlにおける１−ア
ミノ−5,6,7,8−テトラヒドロナフチル4.418gの溶液に
加え、生成した沈殿物を別し、溶剤を除去し、そして
残留物Ａを得、これをエーテル中に溶解させる。固体Ｂ
として残留するフラクシヨンを過する。液を0.1N塩
酸の溶液と重炭酸ナトリウムの飽和溶液と水と次いで塩
化ナトリウムの飽和溶液とで洗浄する。乾燥後、エーテ
ルを除去し、そして0.750gの残留物（フラクシヨンＣ）
を得る。上記のように得られた固体フラクシヨンを塩化
メチレンで溶解させ、0.1N塩酸溶液と重炭酸ナトリウム
飽和溶液と次いで水とで洗浄する。乾燥後、溶剤を減圧
除去する。残留物を水銀柱10-2mmの下で16時間乾燥し、
3.4gの粗生成物（フラクシヨンＤ）を得る。２つのフラ
クシヨン（Ｃ及びＤ）を合し、１のエーテル中に溶解
させ、得られる溶液を活性炭素で処理し、過し、そし
て濃縮する。ペンタンから再結晶化させて、3.617gの求
める生成物を得る。Analytical value: C 13 H 17 NOS, molecular weight 235.350 Calculated value: C% 66.34 H% 7.28 N% 5.96 S% 13.62 Measured value: 66.4 7.4 6 13.6 Example 17: 3-acetylthio-N- (5,6,7,8 -Tetrahydro-1-naphthyl) propanamide 3- (acetylthio) propane prepared as described in Step A of Example 9 in 150 ml of methylene chloride under argon and stirring at -7 ° C to -10 ° C for 30 minutes. A solution of 2.5 g of acid chromide is added to a solution of 4.418 g of 1-amino-5,6,7,8-tetrahydronaphthyl in 150 ml of methylene chloride, the precipitate formed is separated off, the solvent is removed and the residue A is removed. Obtained and this is dissolved in ether. Solid B
As the remaining fraction. The solution is washed with a solution of 0.1N hydrochloric acid, a saturated solution of sodium bicarbonate, water and then a saturated solution of sodium chloride. After drying, the ether was removed and 0.750 g of residue (Fracion C)
To get The solid fraction obtained as above is dissolved in methylene chloride and washed with 0.1N hydrochloric acid solution, saturated sodium bicarbonate solution and then water. After drying, the solvent is removed under reduced pressure. The residue was dried under 10 -2 mm of mercury for 16 hours,
3.4 g of crude product (Fluxion D) are obtained. The two fractions (C and D) are combined, dissolved in 1 ether and the resulting solution is treated with activated carbon, passed and concentrated. Recrystallisation from pentane gives 3.617 g of the expected product.

例18:3−メルカプト−Ｎ−（5,6,7,8−テトラヒドロ−
１−ナフチル）プロパンアミド −５℃〜−10℃で30分間かけてアルゴン下かつ撹拌下
に、130mlの0.1N水酸化ナトリウム溶液をメタノール600
mlにおける例17で得られた生成物3.617gの溶液に加え
る。この温度で撹拌下に１時間放置した後、130mlの0.1
N塩酸を加え、そしてメタノールを除去する。得られた
沈殿物を過し、次いで水銀柱10-2mmにて４時間乾燥す
る。2.890gの生成物が得られ、これはまだ或る程度の出
発化合物を含有する。沈殿物の加水分解を同一条件下
で、250mlのメタノールと130mlの0.1N水酸化ナトリウム
とを用いて反復する。温度を０℃となし、沈殿物を過
する。生成物をシリカ上でのクロマトグラフにかけ、次
いで順次に塩化メチレン及び次いで塩化メチレンとシク
ロヘキサンとの混合物（７−３）で溶出することにより
生成物を精製する。1.170gの求める生成物が得られる。
融点106℃。Example 18: 3-Mercapto-N- (5,6,7,8-tetrahydro-
1-naphthyl) propanamide 130 ml of 0.1N sodium hydroxide solution in methanol 600 at -5 ° C to -10 ° C for 30 minutes under argon and stirring.
Add to a solution of 3.617 g of the product obtained in Example 17 in ml. After standing for 1 hour at this temperature with stirring, 130 ml of 0.1
N hydrochloric acid is added and the methanol is removed. The precipitate obtained is filtered and then dried at 10 -2 mm of mercury for 4 hours. 2.890 g of product are obtained, which still contains some starting compound. The hydrolysis of the precipitate is repeated under the same conditions with 250 ml of methanol and 130 ml of 0.1N sodium hydroxide. Bring the temperature to 0 ° C. and pass the precipitate. The product is purified by chromatography on silica, then eluting successively with methylene chloride and then a mixture of methylene chloride and cyclohexane (7-3). 1.170 g of the expected product is obtained.
Melting point 106 ° C.

分析値:C13H17NOS:235.350 計算値:C％66.34 Ｈ％7.28 Ｓ％13.62 Ｎ％5.95 実測値： 66.5 7.5 13.4 5.9 例19:α−〔（アセチルチオ）メチル〕−Ｎ−〔１−
（フエニルメチル）−ピペリジン−４−イル〕ベンゼン
プロパンアミド 2gの１−（フエニルメチル）−４−アミノピペリジンを
100mlの塩化メチレン中に溶解し、次いで7.19gのトリエ
チルアミンを滴加する。溶液を−10℃まで冷却し、次い
で塩化メチレン100mlに溶解させたα−（アセチルチオ
メチル）−ベンゼンプロパノイル1.82gを加え、−10℃
に３時間保つ後に温度を上昇させ、溶剤を25℃にて蒸発
させ、そして残留物をエチルエーテルで溶解する。有機
相を過し、水洗し、脱水し、そして溶剤を蒸発させ
る。2.73gの求める生成物が得られ、これをシリカ上で
クロマトグラフにかけ、２％のメタノールを含有する酢
酸エチルと塩化メチレンとの混合物（１−１）で溶出さ
せて、1.7gの生成物を得る。融点78℃。Analytical value: C 13 H 17 NOS: 235.350 Calculated value: C% 66.34 H% 7.28 S% 13.62 N% 5.95 Found value: 66.5 7.5 13.4 5.9 Example 19: α-[(acetylthio) methyl] -N- [1-
(Phenylmethyl) -piperidin-4-yl] benzenepropanamide 2 g of 1- (phenylmethyl) -4-aminopiperidine
Dissolve in 100 ml of methylene chloride, then add 7.19 g of triethylamine dropwise. The solution was cooled to -10 ° C, then 1.82 g of α- (acetylthiomethyl) -benzenepropanoyl dissolved in 100 ml of methylene chloride was added, and -10 ° C.
After 3 hours at room temperature the temperature is raised, the solvent is evaporated at 25 ° C. and the residue is taken up with ethyl ether. The organic phase is passed, washed with water, dried and the solvent is evaporated. 2.73 g of the expected product are obtained, which is chromatographed on silica, eluting with a mixture of ethyl acetate and methylene chloride (1-1) containing 2% methanol, giving 1.7 g of product. obtain. Melting point 78 [deg.] C.

例20:α−（メルカプトメチル）−Ｎ−〔１−（フエニ
ルメチル）−ピペリジン−４−イル〕ベンゼンプロパン
アミド メタノール82ml中に溶解させた例19で得られた生成物1.
7gと41mlの0.1N水酸化ナトリウムとを用い、例４に記載
したように操作して、シリカ上でのクロマトグラフイー
により精製し、15％のメタノールを含有する酢酸エチル
と塩化メチレンとの混合物（１−１）で溶出させた後、
1.17gの求める生成物が得られる。融点114℃。Example 20: α- (mercaptomethyl) -N- [1- (phenylmethyl) -piperidin-4-yl] benzenepropanamide The product obtained in Example 19 dissolved in 82 ml of methanol 1.
A mixture of ethyl acetate and methylene chloride containing 15% methanol, purified by chromatography on silica, operating as described in Example 4, using 7 g and 41 ml of 0.1 N sodium hydroxide. After eluting with (1-1),
1.17 g of the expected product is obtained. Melting point 114 ° C.

分析値:C22H28N2OS:368.544 計算値:C％71.6 Ｈ％7.6 Ｎ％7.6 Ｓ％8.7 実測値： 71.6 7.7 7.6 8.9 例21:α−〔（アセチルチオ）メチル〕−Ｎ−〔（ピリ
ジン−３−イル）−メチル〕ベンゼンプロパンアミド 38gの３−ピコリルアミンと350mlのエチルエーテルとを
混合し、０℃まで冷却し、次いで30分間かけてエチルエ
ーテル350mlに溶解させたα−（アセチルチオメチル）
ベンゼンプロパノイル2.8gの溶液を導入する。温度を１
時間上昇させ、200mlの水を加え、次いでpH8−９が得ら
れるまで重炭酸ナトリウムを加える。デカントした後、
有機相を水洗し、脱水し、そして溶剤を蒸発させる。3.
38gの求める生成物が得られる。融点80℃。Analytical value: C 22 H 28 N 2 OS: 368.544 Calculated value: C% 71.6 H% 7.6 N% 7.6 S% 8.7 Actual value: 71.6 7.7 7.6 8.9 Example 21: α-[(acetylthio) methyl] -N-[( Pyridin-3-yl) -methyl] benzenepropanamide 38 g of 3-picolylamine and 350 ml of ethyl ether were mixed, cooled to 0 ° C. and then α- (acetyl) dissolved in 350 ml of ethyl ether over 30 minutes. Thiomethyl)
A solution of 2.8 g of benzenepropanoyl is introduced. Temperature 1
The time is increased and 200 ml of water are added, followed by sodium bicarbonate until a pH of 8-9 is obtained. After decanting
The organic phase is washed with water, dried and the solvent is evaporated. 3.
38 g of the expected product are obtained. Melting point 80 ° C.

例22:α−（メルカプトメチル）−Ｎ−〔（ピリジン−
３−イル）−メチル〕ベンゼンプロパンアミド メタノール200mlに溶解させた例21で得られる生成物3.3
gと100mlの0.1N水酸化ナトリウムとを用い、例４に記載
したように手順を行なう。シリカ上でクロマトグラフに
かけ、酢酸エチルと塩化メチレンとの混合物（９−１）
で溶出して精製した後、23gの求める生成物を得る。融
点70℃。Example 22: α- (mercaptomethyl) -N-[(pyridine-
3-yl) -methyl] benzenepropanamide The product obtained in Example 21 dissolved in 200 ml of methanol 3.3
The procedure is carried out as described in Example 4 with g and 100 ml of 0.1 N sodium hydroxide. Chromatograph on silica, mixture of ethyl acetate and methylene chloride (9-1)
After elution with and purification, 23 g of the expected product is obtained. Melting point 70 ° C.

2gの生成物を5mlの塩化メチレンに溶解させ、そして300
mlのエーテルを加える。０℃まで冷却した後、さらに20
0mlのエーテルを加え、次いで30分間かけてエーテル250
mlにおける24N塩酸のエーテル溶液3.3mlを加える。15分
間撹拌した後、溶剤を除去し、結晶をエーテルで洗浄
し、そして乾燥する。2.02gの求める生成物が得られ
る。融点50℃以下。Dissolve 2 g of product in 5 ml of methylene chloride and
Add ml ether. After cooling to 0 ° C, another 20
Add 0 ml ether, then 250 ether over 30 minutes
Add 3.3 ml of 24N hydrochloric acid in ether solution in ml. After stirring for 15 minutes, the solvent is removed, the crystals are washed with ether and dried. 2.02 g of the expected product is obtained. Melting point 50 ° C or less.

分析値:C16H18N2OS HCl:322.861 計算値：C%59.52 H%5.93 N%8.68 S%9.93 Cl%10.98 実測値： 59.1 5.9 8.7 9.7 11.1 例23:α−〔（アセチルチオ）メチル〕−Ｎ−〔ピリジ
ン−４−イル）−メチル〕ベンゼンプロパンアミド 2.8gの４−ピコリルアミンと3.34gの酸クロライドとを
用いて例21に記載したように操作することにより、3.75
gの求める生成物を得る。融点96℃。Analytical value: C 16 H 18 N 2 OS HCl: 322.861 Calculated value: C% 59.52 H% 5.93 N% 8.68 S% 9.93 Cl% 10.98 Measured value: 59.1 5.9 8.7 9.7 11.1 Example 23: α-((acetylthio) methyl) -N- [Pyridin-4-yl) -methyl] benzenepropanamide 3.75 by operating as described in Example 21 with 2.8 g of 4-picolylamine and 3.34 g of acid chloride.
Obtain the desired product of g. Melting point 96 ° C.

例24:α−（メルカプトメチル）−Ｎ−〔ピリジン−４
−イル）メチル〕−ベンゼンプロパンアミド メタノール22.5mlに溶解した例23で得られた生成物3.7g
と115mlの0.1N水酸化ナトリウムとを用い、例４に記載
したように手順を行なう。3.12gの求める生成物が得ら
れる。この生成物2.5gを最小量の塩化メチレン中に溶解
させ、次いで１のエチルエーテルを加える。０℃まで
冷却した後、30分間かけてエーテル500mlにおける2.4N
塩酸のエーテル溶液4mlを撹拌しながら15分間かけて加
える。次いで溶剤を蒸発させ、生成物をアセトニトリル
から結晶化させて、2gの求める生成物を得る。融点：約
145〜150℃。Example 24: α- (mercaptomethyl) -N- [pyridine-4
-Yl) methyl] -benzenepropanamide 3.7 g of the product obtained in Example 23 dissolved in 22.5 ml of methanol
And 115 ml of 0.1N sodium hydroxide are used and the procedure is carried out as described in Example 4. 3.12 g of the expected product is obtained. 2.5 g of this product are dissolved in a minimum amount of methylene chloride and then 1 ethyl ether is added. After cooling to 0 ° C, 2.4N in 500ml ether over 30 minutes
Add 4 ml of a solution of hydrochloric acid in ether over 15 minutes with stirring. Then the solvent is evaporated and the product is crystallized from acetonitrile to give 2 g of the desired product. Melting point: approx.
145-150 ° C.

分析値:C16H18N2OS HCl:322.861 計算値：C%59.52 H%5.93 N%8.68 S%9.93 Cl%10.98 実測値： 59.5 6.0 8.6 9.7 11.1 例25:α−〔（アセチルチオ）メチル〕−Ｎ−〔（ピリ
ジン−２−イル）−メチル〕ベンゼンプロパンアミド 2.8gの２−ピコリルアミンと3.34gの酸クロライドとを
用いて、例21に記載したように操作することにより、3.
98gの求める生成物を得る。融点57℃。Analytical value: C 16 H 18 N 2 OS HCl: 322.861 Calculated value: C% 59.52 H% 5.93 N% 8.68 S% 9.93 Cl% 10.98 Measured value: 59.5 6.0 8.6 9.7 11.1 Example 25: α-((acetylthio) methyl) -N-[(pyridin-2-yl) -methyl] benzenepropanamide By operating as described in Example 21, using 2.8 g of 2-picolylamine and 3.34 g of acid chloride, 3.
98 g of the expected product are obtained. Melting point 57 ° C.

例26:α−（メルカプトメチル−Ｎ−〔（ピリジン−２
−イル）メチル〕−ベンゼンプロパンアミド塩酸塩 メタノール250mlに溶解させた例25で得られる生成物3.9
2gと120mlの0.1N水酸化ナトリウムとを用いて例４に記
載したように手順を行なう。求める生成物のベース3.44
gが得られ、この生成物を800mlのエーテル中に溶解さ
せ、次いで過し、そしてエーテル200mlにおける2.4N
塩酸のエーテル溶液5.5mlを加える。10分間撹拌した
後、溶剤を蒸発させ、そして生成物をアセトニトリルか
ら結晶化させる。2.83gの求める生成物が得られる。融
点135〜140℃。Example 26: α- (mercaptomethyl-N-[(pyridine-2
-Yl) methyl] -benzenepropanamide hydrochloride product 3.9 obtained in Example 25 dissolved in 250 ml methanol
The procedure is carried out as described in Example 4 with 2 g and 120 ml of 0.1 N sodium hydroxide. Product base sought 3.44
g were obtained, the product was dissolved in 800 ml of ether, then passed and 2.4 N in 200 ml of ether.
5.5 ml of a solution of hydrochloric acid in ether are added. After stirring for 10 minutes, the solvent is evaporated and the product is crystallized from acetonitrile. 2.83 g of the expected product are obtained. Melting point 135-140 ° C.

分析値:C16H18N2OS、HCl:322.861 計算値：C%59.52 H%5.93 N%8.68 S%9.93 Cl%10.98 実測値： 59.6 5.8 8.5 9.7 11.1 例27:医薬組成物 次の配合により錠剤を作成した： 例２の化合物 ……200mg 右量の錠剤に充分な量の補形薬 ……350mg （補形薬の詳細：乳糖、澱粉、ステアリン酸マグネシウ
ム、タルク）。Analytical value: C 16 H 18 N 2 OS, HCl: 322.861 Calculated value: C% 59.52 H% 5.93 N% 8.68 S% 9.93 Cl% 10.98 Measured value: 59.6 5.8 8.5 9.7 11.1 Example 27: Pharmaceutical composition Tablets were made: Compound of Example 2 ...... 200 mg A sufficient amount of excipients for right amount of tablets ... 350 mg (Details of excipients: lactose, starch, magnesium stearate, talc).

次の配合にしたがい錠剤を作成した： 例22の化合物 ……200mg 右量の錠剤に充分な補形薬 ……350mg （補形薬の詳細：乳糖、澱粉、ステアリン酸マグネシウ
ム、タルク）。Tablets were made according to the following formulation: Compound of Example 22 ...... 200 mg Enough excipient for right dose tablets ... 350 mg (Details of excipients: lactose, starch, magnesium stearate, talc).

生物学的試験 （１） エンケフアリナーゼの投与及び抑制剤の効果の
測定 エンケフアリナーゼの活性をラツテ線条体の膜フラクシ
ヨンにおいて評価する。Biological test (1) Administration of enkephalinase and measurement of inhibitory effect The activity of enkephalinase is evaluated in a membrane fraction of the rat striatum.

線条体を氷上で取り出し、トリス緩衝液0.05M、pH7.4
（容積の20倍）においてホモゲナイズする。最初に1000
gで遠心分離した後、特定フラクシヨンを得、次いで200
00gにて第２の遠心分離を10分間行なう。次いで沈降物
をトリス緩衝液に懸濁させ、４℃に保つ。クーマシーの
「au blue」法にしたがつて蛋白質投与を行なう。Remove the striatum on ice and use Tris buffer 0.05M, pH7.4
Homogenize at (20 times volume). First 1000
After centrifuging at g, a specific fraction is obtained, then 200
Perform a second centrifugation at 00g for 10 minutes. The pellet is then suspended in Tris buffer and kept at 4 ° C. Protein is administered according to Coomassie's “au blue” method.

25℃にて15分間予備培養した後、所定量の蛋白質を、予
め精製した第１アミノ酸、１ミリモルのプロマイシン及
び試験化合物につきトリス緩衝液中でトリチル化した20
ノナモルのロイシン−エンセフアリンの存在下に25℃に
て15分間培養する。0.2N塩酸を加えて加水分解反応を停
止させ、そして培養物を加熱（95℃にて15分間）による
除蛋白にかける。これらの条件下において、反応速度は
直線的である。After preincubation for 15 minutes at 25 ° C., a predetermined amount of protein was tritylated in pre-purified primary amino acid, 1 mmol puromycin and test compound in Tris buffer.
Incubate for 15 minutes at 25 ° C. in the presence of nonamol leucine-encephalin. The hydrolysis reaction is stopped by adding 0.2 N hydrochloric acid, and the culture is subjected to deproteinization by heating (95 ° C. for 15 minutes). Under these conditions, the reaction rate is linear.

加水分解により得られたトリチル化代謝物をポラパツク
Ｑでのカラムクロマトグラフイーによりエンセフアリン
から分離する。これらをトリスタンポンで溶出させる一
方、エンセフアリンをカラム上に保持し、次いでエタノ
ール相中に回収する。The tritylated metabolite obtained by hydrolysis is separated from encephalin by column chromatography on Polapack Q. While these are eluted with Tristanpon, encephalin is retained on the column and then recovered in the ethanol phase.

種々異なる化合物の活性を50％阻止濃度（IC50）として
表わす。The activity of the different compounds is expressed as the 50% inhibitory concentration (IC50).

結 果 （２） 炎症組織に対する麻酔試験 （ランダール及びセリツト（１）の技術の変法） この技術は、痛みに対する感受性の閾値を炎症により低
下させたラツテにつき麻酔作用を検査することからなつ
ている。Result (2) Anesthesia test on inflamed tissue (a modified version of the technique of Randall and Seritt (1)) This technique consists of examining the anesthetic action of latte whose threshold of sensitivity to pain is lowered by inflammation.

このラツテは、後足の足底腱膜にカラゲニン（0.25mg/
足１本）を注入して得る。機械的圧力を足の裏面に加え
かつ麻酔計により定期的に増大させて痛みを生ぜしめ
る。This ratte is carrageenin (0.25mg /
Obtained by injecting one foot). Mechanical pressure is applied to the underside of the foot and periodically increased by anesthesia to cause pain.

足の退縮反応又は動物の鳴声反応を生ぜしめるのに必要
な圧力により、痛みの閾値を評価する。The pain threshold is assessed by the pressure required to produce the paw withdrawal response or the animal's vocal response.

刺戟物を注入してから４時間後に経口経路により化合物
を投与し、そして痛み閾値の測定を刺戟物の注入直後及
び処理の１時間後に行なう。Compounds are administered by the oral route 4 hours after infusion of stimulus and pain threshold measurements are taken immediately after infusion of stimulus and 1 hour after treatment.

（１） 〔エル・デイー・ランダール及びジエー・ジエ
ー・セリツト、「炎症組織に対する麻酔の測定方法」、
Arch.Int.Pharmacodyn、（1957）、第111巻、第409
頁〕。(1) [Ldee Landal and JAE Seritt, "Method of measuring anesthesia for inflamed tissue",
Arch.Int.Pharmacodyn, (1957), Volume 111, Volume 409
page〕.

結 果 Result

───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.5 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ｃ０７Ｃ 327/32 7106−4Ｈ Ｃ０７Ｄ 211/26 9165−4Ｃ 211/56 9165−4Ｃ 213/40 ─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. 5 Identification code Office reference number FI Technical display location C07C 327/32 7106-4H C07D 211/26 9165-4C 211/56 9165-4C 213/40

Claims (9)

【特許請求の範囲】[Claims] 【請求項１】式（Ｉ）： ［式中、R1は水素原子又は を示し、 Ｒ′１は１〜５個の炭素原子を有するアルキル基であ
り、ｎは１の整数を示し、R2は水素原子、１〜５個の炭
素原子を有するアルキル基又はアリールアルキル基を示
し、ｍは０〜２の範囲で変化しうる整数を示し、R3は３
〜12個の炭素原子を有するシクロアルキル基を示すが、
R2及びR1が同時に水素原子を示しさらにｎ＝１かつｍ＝
０である場合にはシクロヘキシル基を示すことができ
ず、又はR3はフェニル、ジヒドロインデニル、ナフチル
若しくはテトラヒドロナフチル基を示し、又はR3は2,3
若しくは４−ピリジニル基を示し、又はフェニルメチル
基により置換されたピペリジニル基を示し、ただし （ａ） ｍ＝ｎ＝１かつR1=R2=Ｈ （ｂ） ｍ＝ｎ＝１、 かつR2=CH3である場合、 R3はフェニル基でない］ を有する化合物並びにその酸付加塩。1. Formula (I): [In the formula, R 1 is a hydrogen atom or R ′ 1 is an alkyl group having 1 to 5 carbon atoms, n is an integer of 1, R 2 is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms or an arylalkyl group. , M is an integer that can vary in the range of 0 to 2, and R 3 is 3
Represents a cycloalkyl group having ~ 12 carbon atoms,
R 2 and R 1 simultaneously represent a hydrogen atom, and n = 1 and m =
When it is 0, it cannot represent a cyclohexyl group, or R 3 represents a phenyl, dihydroindenyl, naphthyl or tetrahydronaphthyl group, or R 3 represents 2,3
Or a 4-pyridinyl group, or a piperidinyl group substituted with a phenylmethyl group, wherein (a) m = n = 1 and R 1 = R 2 = H (b) m = n = 1, And R 2 = CH 3 , R 3 is not a phenyl group] and an acid addition salt thereof. 【請求項２】R1が水素であることを特徴とする特許請求
の範囲第１項記載の式（Ｉ）を有する化合物。2. A compound of formula (I) according to claim 1 characterized in that R 1 is hydrogen. 【請求項３】R1がアセチル基であることを特徴とする特
許請求の範囲第１項記載の式（Ｉ）を有する化合物。3. A compound having the formula (I) according to claim 1, characterized in that R 1 is an acetyl group. 【請求項４】ｎ＝１でありかつR2がベンジル基又は水素
原子であることを特徴とする特許請求の範囲第１〜３項
のいずれかに記載の式（Ｉ）を有する化合物。4. A compound having the formula (I) according to any one of claims 1 to 3, wherein n = 1 and R 2 is a benzyl group or a hydrogen atom. 【請求項５】ｍ＝１又は２であり、かつR3がフェニル基
若しくはピリジニル基を示すことを特徴とする特許請求
の範囲第１〜４項のいずれかに記載の式（Ｉ）を有する
化合物。5. The formula (I) according to any one of claims 1 to 4, wherein m = 1 or 2 and R 3 represents a phenyl group or a pyridinyl group. Compound. 【請求項６】Ｎ−シクロヘキシル−α−（メルカプトメ
チル）ベンゼンプロパンアミド、 α−（メルカプトメチル）−Ｎ−（２−フェニルエチ
ル）ベンゼンプロパンアミド、 Ｎ−（2,3−ジヒドロ−1H−インデン−２−イル）−３
−メルカプトプロパンアミド、 α−（メルカプトメチル）−Ｎ−（２−ピリジニルメチ
ル）ベンゼンプロパンアミド、 α−（メルカプトメチル）−Ｎ−（３−ピリジニルメチ
ル）ベンゼンプロパンアミド、 α−（メルカプトメチル）−Ｎ−（４−ピリジニルメチ
ル）ベンゼンプロパンアミド 並びにその酸付加塩である特許請求の範囲第１〜５項の
いずれかに記載の式（Ｉ）を有する化合物。6. N-cyclohexyl-α- (mercaptomethyl) benzenepropanamide, α- (mercaptomethyl) -N- (2-phenylethyl) benzenepropanamide, N- (2,3-dihydro-1H-indene -2-yl) -3
-Mercaptopropanamide, α- (mercaptomethyl) -N- (2-pyridinylmethyl) benzenepropanamide, α- (mercaptomethyl) -N- (3-pyridinylmethyl) benzenepropanamide, α- (mercaptomethyl) -N- A compound having the formula (I) according to any one of claims 1 to 5, which is (4-pyridinylmethyl) benzenepropanamide and an acid addition salt thereof. 【請求項７】式（Ｉ）： ［式中、R1は水素原子又は を示し、 Ｒ′１は１〜５個の炭素原子を有するアルキル基であ
り、ｎは１の整数を示し、R2は水素原子、１〜５個の炭
素原子を有するアルキル基又はアリールアルキル基を示
し、ｍは０〜２の範囲で変化しうる整数を示し、R3は３
〜12個の炭素原子を有するシクロアルキル基を示すが、
R2及びR1が同時に水素原子を示しさらにｎ＝１かつｍ＝
０である場合にはシクロヘキシル基を示すことができ
ず、又はR3はフェニル、ジヒドロインデニル、ナフチル
若しくはテトラヒドロナフチル基を示し、又はR3は2,3
若しくは４−ピリジニル基を示し、又はフェニルメチル
基により置換されたピペリジニル基を示し、ただし （ａ） ｍ＝ｎ＝１かつR1=R2=Ｈ （ｂ） ｍ＝ｎ＝１、 かつR2=CH3である場合、 R3はフェニル基でない］ を有する化合物並びにその酸付加塩を製造するに際し、
式（II）： ［式中、Ｒ′１及びR2は上記の意味を有する］ を有する酸又はこの酸の官能性誘導体を式（III）： HaN−（CH2）ｍ−R3 （III） ［式中、R3及びｍは上記の意味を有する］ を有する化合物の作用にかけて式（Ｉ）［式中、 であり、Ｒ′１並びにR2、R3及びｍは上記の意味を有
し、かつｎ＝１である］を有する化合物を得、この式
（Ｉ）を有する化合物を必要に応じけん化して、R1が水
素を示す式（Ｉ）を有する化合物及び必要に応じ酸の作
用により塩にされた式（Ｉ）を有する化合物を得ること
を特徴とする式（Ｉ）を有する化合物の製造方法。7. Formula (I): [In the formula, R 1 is a hydrogen atom or R ′ 1 is an alkyl group having 1 to 5 carbon atoms, n is an integer of 1, R 2 is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms or an arylalkyl group. , M is an integer that can vary in the range of 0 to 2, and R 3 is 3
Represents a cycloalkyl group having ~ 12 carbon atoms,
R 2 and R 1 simultaneously represent a hydrogen atom, and n = 1 and m =
When it is 0, it cannot represent a cyclohexyl group, or R 3 represents a phenyl, dihydroindenyl, naphthyl or tetrahydronaphthyl group, or R 3 represents 2,3
Or a 4-pyridinyl group, or a piperidinyl group substituted with a phenylmethyl group, wherein (a) m = n = 1 and R 1 = R 2 = H (b) m = n = 1, And R 2 = CH 3 , R 3 is not a phenyl group] in the production of a compound and an acid addition salt thereof.
Formula (II): [Wherein R ′ 1 and R 2 have the above meanings] or a functional derivative of this acid is represented by formula (III): HaN— (CH 2 ) m—R 3 (III) R 3 and m have the above-mentioned meanings] and the formula (I) [wherein And R ′ 1 and R 2 , R 3 and m have the above-mentioned meanings and n = 1], and saponify the compound having the formula (I) if necessary. , A compound of formula (I) in which R 1 represents hydrogen and a compound of formula (I), optionally salted by the action of an acid, to obtain a compound of formula (I) . 【請求項８】式（Ｉ）： ［式中、R1は水素原子又は を示し、Ｒ′１は１〜５個の炭素原子を有するアルキル
基であり、ｎは１の整数を示し、R2は水素原子、１〜５
個の炭素原子を有するアルキル基又はアリールアルキル
基を示し、ｍは１又は２の整数を示し、R3は３〜12個の
炭素原子を有するシクロアルキル基を示すが、R2及びR1
が同時に水素原子を示しさらにｎ＝１かつｍ＝０である
場合にはシクロヘキシル基を示すことができず、又はR3
はフェニル、ジヒドロインデニル、ナフチル若しくはテ
トラヒドロナフチル基を示し、又はR3は2,3若しくは４
−ピリジニル基を示し、又はフェニルメチル基により置
換されたピペリジニル基を示し、ただし （ａ） ｍ＝ｎ＝１かつR1=R2=Ｈ （ｂ） ｍ＝ｎ＝１、 かつR2=CH3である場合、 R3はフェニル基でない］ を有する化合物並びにその酸付加塩を製造するに際し、
式（IV）： ［式中、Ｘはハロゲン原子でありかつｎ及びR2は上記の
意味を有する］ を有する酸又はその官能性誘導体を式（III）： H2N−（CH2）ｍ−R3 （III） ［式中、R3及びｍは上記の意味を有する］ を有する化合物の作用にかけて式（Ｖ）： ［式中、Ｘ、ｎ、ｍ、R2及びR3は上記の意味を有する］ の化合物を得、これを式（VI）： ［式中、Ｒ′１は上記の意味を有する］ を有するチオ酸の作用にかけて式（Ｉ）［式中、 でありかつＲ′１、R2、R3、 ｎ及びｍは上記の意味を有する］を有する化合物を得、
この式（Ｉ）を有する化合物を必要に応じけん化してR1
が水素原子を示す式（Ｉ）を有する化合物を得、かつ必
要に応じこの式（Ｉ）を有する化合物を酸の作用により
塩にすることを特徴とする式（Ｉ）を有する化合物の製
造方法。8. Formula (I): [In the formula, R 1 is a hydrogen atom or R'1 is an alkyl group having 1 to 5 carbon atoms, n is an integer of 1, R 2 is a hydrogen atom, 1 to 5
Represents an alkyl group or arylalkyl group having 4 carbon atoms, m represents an integer of 1 or 2, R 3 represents a cycloalkyl group having 3 to 12 carbon atoms, and R 2 and R 1
Simultaneously represent a hydrogen atom, and when n = 1 and m = 0, cannot represent a cyclohexyl group, or R 3
Represents a phenyl, dihydroindenyl, naphthyl or tetrahydronaphthyl group, or R 3 is 2, 3 or 4
A pyridinyl group or a piperidinyl group substituted by a phenylmethyl group, wherein (a) m = n = 1 and R 1 = R 2 = H (b) m = n = 1, And R 2 = CH 3 , R 3 is not a phenyl group] in the production of a compound and an acid addition salt thereof.
Formula (IV): [Wherein X is a halogen atom and n and R 2 have the above meanings] or a functional derivative thereof is represented by the formula (III): H 2 N- (CH 2 ) m-R 3 (III ) [Wherein R 3 and m have the above-mentioned meanings], and the formula (V): [Wherein, X, n, m, R 2 and R 3 have the above meanings], and the compound of the formula (VI): [In the formula, R ′ 1 has the above-mentioned meanings] The formula (I) [in the formula, By and and R '1, R 2, R 3, n and m are to give the compound having a have the meanings mentioned above,
The compound having the formula (I) is optionally saponified to give R 1
A method for producing a compound having the formula (I), which comprises obtaining a compound having the formula (I) in which is a hydrogen atom, and optionally converting the compound having the formula (I) into a salt by the action of an acid. . 【請求項９】式（Ｉ）： ［式中、R1は水素原子又は を示し、 Ｒ′１は１〜５個の炭素原子を有するアルキル基であ
り、ｎは１の整数を示し、R2は水素原子、１〜５個の炭
素原子を有するアルキル基又はアリールアルキル基を示
し、ｍは０〜２の範囲で変化しうる整数を示し、R3は３
〜12個の炭素原子を有するシクロアルキル基を示すが、
R2及びR1が同時に水素原子を示しさらにｎ＝１かつｍ＝
０である場合にはシクロヘキシル基を示すことができ
ず、又はR3はフェニル基を示し、又はR3は2,3若しくは
４−ピリジニル基を示し、ただし、 （ａ） ｍ＝ｎ＝１かつR1=R2=Ｈ （ｂ） ｍ＝ｎ＝１、 かつR2=CH3である場合、 R3はフェニル基でない］ を有する化合物並びに医薬上許容しうる酸によるその付
加塩の少なくとも１種を活性成分として含有する鎮痛
剤。9. Formula (I): [In the formula, R 1 is a hydrogen atom or R ′ 1 is an alkyl group having 1 to 5 carbon atoms, n is an integer of 1, R 2 is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms or an arylalkyl group. , M is an integer that can vary in the range of 0 to 2, and R 3 is 3
Represents a cycloalkyl group having ~ 12 carbon atoms,
R 2 and R 1 simultaneously represent a hydrogen atom, and n = 1 and m =
When it is 0, it cannot represent a cyclohexyl group, or R 3 represents a phenyl group, or R 3 represents a 2,3 or 4-pyridinyl group, provided that (a) m = n = 1 and R 1 = R 2 = H (b) m = n = 1, And R 2 = CH 3 , R 3 is not a phenyl group], and an analgesic containing as an active ingredient at least one of a pharmaceutically acceptable acid addition salt thereof.
JP60059719A 1984-03-29 1985-03-26 1'ω-mercaptopropanamide and its salt, method for producing the same, and drug containing the same Expired - Lifetime JPH0694456B2 (en)

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Application Number Priority Date Filing Date Title
FR8404917A FR2562068B1 (en) 1984-03-29 1984-03-29 NOVEL DERIVATIVES OF O-MERCAPTOPROPANAMIDE AND ITS HOMOLOGUES, THEIR PREPARATION METHOD, THEIR APPLICATION AS MEDICAMENTS, THE COMPOSITIONS CONTAINING THEM AND THE NEW INTERMEDIATES OBTAINED
FR84-4917 1984-03-29

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JPH0694456B2 true JPH0694456B2 (en) 1994-11-24

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US5223516A (en) * 1990-03-22 1993-06-29 E. R. Squibb & Sons, Inc. 3,3,3-trifluoro-2-mercaptomethyl-N-tetrazolyl substituted propanamides and method of using same
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CA1182818A (en) * 1980-05-30 1985-02-19 Joseph E. Sundeen N-substituted mercaptoacyl propionamides
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